154 lb Leg tumor

1. 154 lb Leg tumor Regulation of Cell DivisionTarget: I can describe what happens when uncontrolled cell growth occurs.

2. Coordination of cell division • A multicellular organism needs to coordinate cell division across different tissues & organs • critical for normal growth, development & maintenance • coordinate timing of cell division • coordinate rates of cell division • not all cells can have the same cell cycle

3. M anaphase metaphase telophase prophase C G2 interphase (G1, S, G2 phases) mitosis (M) cytokinesis (C) G1 S Frequency of cell division • Frequency of cell division varies by cell type • embryo • cell cycle < 20 minute • skin cells • divide frequently throughout life • 12-24 hours cycle • liver cells • retain ability to divide, but keep it in reserve • divide once every year or two • mature nerve cells & muscle cells • do not divide at all after maturity • permanently in G0

4. Checkpoint control system • Checkpoints • cell cycle controlled by STOP & GO chemical signals at critical points • signals indicate if key cellular processes have been completed correctly

5. Checkpoint control system • 3 major checkpoints: • G1/S • can DNA synthesis begin? • G2/M • has DNA synthesis been completed correctly? • commitment to mitosis • spindle checkpoint • are all chromosomes attached to spindle? • can sister chromatids separate correctly?

6. Activation of cell division • How do cells know when to divide? • cell communication signals • chemical signals in cytoplasm give cue • signals usually mean proteins • activators • inhibitors experimental evidence: Can you explain this?

7. “Go-ahead” signals • Protein signals that promote cell growth & division • internal signals • “promoting factors” • external signals • “growth factors” • Primary mechanism of control • phosphorylation • kinase enzymes • either activates or inactivates cell signals

8. inactivated Cdk Cell cycle signals • Cell cycle controls • cyclins • regulatory proteins • levels cycle in the cell • Cdks • cyclin-dependent kinases • phosphorylates cellular proteins • activates or inactivates proteins • Cdk-cyclin complex • triggers passage through different stages of cell cycle activated Cdk

9. Leland H. Hartwell checkpoints Tim Hunt Cdks Sir Paul Nurse cyclins 1970s-80s | 2001 Cyclins & Cdks • Interaction of Cdk’s & different cyclins triggers the stages of the cell cycle

10. Growth factor signals growth factor nuclear pore nuclear membrane P P cell division cell surface receptor Cdk E2F protein kinase cascade P chromosome P Rb P E2F Rb nucleus cytoplasm

11. Example of a Growth Factor • Platelet Derived Growth Factor (PDGF) • made by platelets in blood clots • binding of PDGF to cell receptors stimulates cell division in connective tissue • heal wounds Don’t forget to mentionerythropoietin!(EPO)

12. Growth Factors and Cancer • Growth factors can create cancers • proto-oncogenes • normally activates cell division • growth factor genes • become oncogenes (cancer-causing) when mutated • if switched “ON” can cause cancer • example: RAS (activates cyclins) • tumor-suppressor genes • normally inhibits cell division • if switched “OFF” can cause cancer • example: p53

13. Cancer & Cell Growth • Cancer is essentially a failure of cell division control • unrestrained, uncontrolled cell growth • What control is lost? • lose checkpoint stops • gene p53 plays a key role in G1/S restriction point • p53 protein halts cell division if it detects damaged DNA • options: • stimulates repair enzymes to fix DNA • forces cell into G0 resting stage • keeps cell in G1 arrest • causes apoptosis of damaged cell p53 is theCell CycleEnforcer p53 discovered at Stony Brook by Dr. Arnold Levine

14. Development of Cancer • Cancer develops only after a cell experiences ~6 key mutations (“hits”) • unlimited growth • turn on growth promoter genes • ignore checkpoints • turn off tumor suppressor genes (p53) • escape apoptosis • turn off suicide genes • immortality = unlimited divisions • turn on chromosome maintenance genes • promotes blood vessel growth • turn on blood vessel growth genes • overcome anchor & density dependence • turn off touch-sensor gene It’s like anout-of-controlcar with manysystems failing!

15. What causes these “hits”? • Mutations in cells can be triggered by • UV radiation • chemical exposure • radiation exposure • heat • cigarette smoke • pollution • age • genetics

16. Tumors • Mass of abnormal cells • Benign tumor • abnormal cells remain at original site as a lump • p53 has halted cell divisions • most do not cause serious problems &can be removed by surgery • Malignant tumor • cells leave original site • lose attachment to nearby cells • carried by blood & lymph system to other tissues • start more tumors =metastasis • impair functions of organs throughout body

17. Traditional treatments for cancers • Treatments target rapidly dividing cells • high-energy radiation • kills rapidly dividing cells • chemotherapy • stop DNA replication • stop mitosis & cytokinesis • stop blood vessel growth

18. New “miracle drugs” • Drugs targeting proteins (enzymes) found only in cancer cells • Gleevec • treatment for adult leukemia (CML)& stomach cancer (GIST) • 1st successful drug targeting only cancer cells withoutGleevec withGleevec Novartes

19. Any Questions??